Growth hormone (GH), also known as somatotropin, is a protein hormone of about 190 amino acids synthesized and secreted by cells called somatotrophs in the anterior pituitary. It is a major participant in control of growth and metabolism. It is also of considerable interest as a pharmaceutical product for use in both humans and animals. The production of GH is modulated by many factors, including stress, nutrition, sleep and GH itself. However, its primary controllers are two hypothalamic hormones:                the growth hormone-releasing factor (GRF or GHRH), a 44 amino acid sequence that stimulates the synthesis and secretion of GH and;        somatostatin (SS), which inhibits GH release in response to GRF.        
It has been shown that the biological activity of GRF (1–44) resides in the N-terminal portion of the peptide. Full intrinsic activity and potency was also demonstrated with GRF (1–29) both in vitro and in vivo. Furthermore, sustained administration of GRF induces the same episodic secretory pattern of GH from the pituitary gland as under normal physiological conditions. Synthetic peptides such as growth hormone releasing peptide (GHRP) as well as peptidomimetics recently developed by Merck and other pharmaceutical companies have demonstrated their capability for stimulating the release of endogenous GH. Another analog a trisubstituted GRF1-29 developed by Hoffmann-La Roche in the mid-80's, [des-amino-Tyr1,D-Ala2,Ala15]-GRF1-29, is a GRF superagonist with a prolonged duration of action.
GH secretagogues (GHSs) are known to stimulate the release of GH from the pituitary through an orphan G-protein-coupled receptor (GHS-R). Recently, another endogenous ligand for GHS-R was identified as ghrelin. It is an octanoylated (28-residue peptide with the n-octanoyl at Ser3) peptide.
Recombinant GH (rGH) was first produced in 1985 and is now commercially available for both medical and veterinary uses. However, the long-term safety of rGH has not yet been determined. Further, several side effects resulting from the use of rGH in human have been reported, i.e., left ventricular mass index, an increase in serum lipoprotein, and a subtle change in immune parameters. Finally, frequent bolus injections of rGH are known to cause a progressive down-regulation of receptors, and thus to a decrease of its efficacy over time.
Besides these practical drawbacks, exogenous GH is species-specific, which limits its advantages in enhancing growth and other beneficial effects in different species, i.e. humans and animals. Small quantities of GRF have been found to cause substantial pituitary release of GH into the blood of treated animals. Thus GRF has great therapeutic utility in those instances where growth hormone is indicated. For example, it may be used in the treatment of hypopituitary dwarfism, diabetes due to GH production abnormalities, and retardation of the aging process. Many other diseases or conditions benefiting from endogenous production or release of GRF are enumerated below. Further, GRF is useful in the field of agriculture. Examples of agricultural uses include enhanced meat production of pigs, cattle or the like to permit earlier marketing. GRF is also known to stimulate milk production in dairy cows.
Up to now, a major drawback associated with the use of peptide-related GH secretagogues is the lack of a suitable technology capable of providing a substantially linear and sustained delivery of GH over prolonged periods of time, e.g., several days to weeks.
GRF (1–29), like many other peptides possessing therapeutic properties, is highly unstable in vivo, which significantly limits its use as pharmaceutical product to promote the release of GH in humans and animals. Because the half-life of GRF 1–29 generally does not exceed 10–13 minutes, it has to be injected in bolus several times a day or infused to be able to sustain measurable GH release.
Significant research efforts have been deployed over the past several years to develop long-acting analogs of GRF. Although several new analogs with improved duration of action have been synthesized, none of them meets the criteria that are required for GH-releasing drugs. Furthermore, no formulation is known to releasing such unstable peptides over a defined period of time in animals or humans.
U.S. Pat. No. 5,846,936 discloses GRF analogs that are said to have enhanced potency, increased enzyme stability and improved half-life stability. The patent mentions that the analogs can be administered with various adjuvants such as serum albumin. The only half-life stability results presented in the patent are in vitro. There is no data on the actual stability of the peptides in vivo.
U.S. Pat. No. 4,963,529 describes a GRF composition, either in the solid or liquid form, comprising GRF and human serum albumin or glycine. The composition may also contain a buffer, and is said to stabilize GRF.
WO 9724445 discloses the fusion of a growth hormone (hGH) with a molecule of recombinant albumin. Such fusion protein is said to have an increased circulatory half-life over unfused growth hormone. A linker, optionally cleavable, may be inserted between the molecule of albumin and the growth hormone, to facilitate binding of the hGH to the receptor.
WO 0069900 discloses a method for the production of peptidase-stabilized peptides. A series of GRF peptides are listed as potential candidates that can be stabilized according to the method disclosed in this application, but none of them are specifically exemplified in the description.
There is therefore a great need to develop a long-lasting compound capable of promoting the release of GH in a subject, animal or human. Such promotion should preferably be sustained over an extended period of time without the undesirable side effects of rGH.